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Evaluation of Potential Pharmacokinetic Drug-Drug Interaction Between Armodafinil and Risperidone in Healthy Adults

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Abstract

Background and Objective

Patients with bipolar I disorder and schizophrenia have an increased risk of obstructive sleep apnea. The effects of armodafinil, a weak cytochrome P450 (CYP) 3A4 inducer, on pharmacokinetics and safety of risperidone, an atypical antipsychotic used to treat major psychiatric illness, were investigated.

Methods

Healthy subjects received 2 mg risperidone alone and after armodafinil pretreatment (titrated to 250 mg/day). Pharmacokinetic parameters were derived from plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone (formed via CYP2D6 and CYP3A4), collected before and over 4 days after risperidone administration, and from steady-state plasma concentrations of armodafinil and its circulating metabolites, R-modafinil acid and modafinil sulfone. Safety and tolerability were assessed.

Results

Thirty-six subjects receiving study drug were evaluable for safety; 34 were evaluable for pharmacokinetics. Risperidone maximum plasma concentration (C max) decreased from mean 16.5 ng/mL when given alone to 9.2 ng/mL after armodafinil pretreatment (geometric mean ratio [90 % CI] 0.55 [0.50–0.61]); area under the plasma concentration-time curve from time 0 to infinity (AUC0–∞) decreased from 92.3 to 44.5 ng·h/mL (geometric mean ratio [90 % CI] 0.51 [0.46–0.55]). C max and AUC0–∞ for 9-hydroxyrisperidone were also reduced (geometric mean ratios [90 % CI] 0.81 [0.77–0.85] and 0.73 [0.69–0.77], respectively). Adverse events were consistent with known safety profiles.

Conclusion

Consistent with CYP3A4 induction, risperidone and 9-hydroxyrisperidone systemic exposure was reduced in the presence of armodafinil. Concomitant armodafinil and risperidone use may necessitate risperidone dosage adjustment, particularly when starting or stopping coadministration of the two drugs. However, any such decision should be based on patient disease state and clinical status.

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Acknowledgments

The authors thank Sarah Mizne, PharmD, of MedVal Scientific Information Services, LLC, Joyce Willetts, PhD, consultant to MedVal Scientific Information Services, LLC, and Kathleen Dorries, PhD, of Peloton Advantage, LLC, for providing medical writing and editorial assistance, funded by Teva Branded Pharmaceutical Products R & D, Inc. (Frazer, PA). Teva provided a full review of the article. The authors also thank Steve Gorman, who oversaw the bioanalytical work, and Cathye Shu, a former Teva employee, for useful discussions of the results. This manuscript was prepared according to the International Society for Medical Publication Professionals’ “Good Publication Practice for Communicating Company-Sponsored Medical Research: The GPP2 Guidelines.” All authors have approved the final article.

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Authors and Affiliations

  1. Sci-Med Bridge, LLC, Malvern, PA, USA

    Mona Darwish

  2. Teva Pharmaceuticals, Frazer, PA, USA

    Mary Bond & Ronghua Yang

  3. Teva Pharmaceuticals, West Chester, PA, USA

    Edward T. Hellriegel & Philmore Robertson

Authors
  1. Mona Darwish
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  2. Mary Bond
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  3. Ronghua Yang
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  4. Edward T. Hellriegel
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  5. Philmore Robertson
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Corresponding author

Correspondence to Mary Bond.

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Disclosure of potential conflicts of interest

This study was sponsored by Teva Branded Pharmaceutical Products R & D, Inc. All authors are employees or former employees of Teva Pharmaceuticals, Inc. MB, PR, and ETH own stock/options in Teva Pharmaceuticals, Inc.

Research involving human participants and/or animals

The protocol was reviewed and approved by an institutional review board (IntegReview, Austin, TX, USA). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee, the 1964 Helsinki declaration and its later amendments or comparable ethical standards, and with the current revision of the International Conference on Harmonisation Good Clinical Practice Guideline.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Darwish, M., Bond, M., Yang, R. et al. Evaluation of Potential Pharmacokinetic Drug-Drug Interaction Between Armodafinil and Risperidone in Healthy Adults. Clin Drug Investig 35, 725–733 (2015). https://doi.org/10.1007/s40261-015-0330-6

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  • DOI: https://doi.org/10.1007/s40261-015-0330-6

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